The class of steroidal horomones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective production control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, and benign prostatic hypertrophy are correlated with elevated androgen levels. Additionally, the incidence of male pattern baldness has been associated with high androgen levels.
Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5-.alpha.-reduced androgens are active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-.alpha.-reduced analogue in these tissues but not in others such as muscle and testis. Steroid 5-.alpha.-reductase is a NADPH-dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by discovery of a genetic steroid 5-.alpha.-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., et al., (1979), J. Steroid Biochem. 11:637-648.
Recognition of the importance of elevated DHT levels in various disease states has stimulated many efforts to synthesize inhibitors of this enzyme.
The first inhibitor described was 4-androsten-3-one-17.beta.-carboxylic acid by Hisa and Voight in 1973. J. Invest. Dermat. 62:224-227. (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-triane was the next inhibitor to be described and also has found utiltiy as an affinity label for 5-.alpha.-reductase. Robaire, B., et al., (1977), J. Steroid Biochem. 8:307-310. (5.alpha.,20-R)-4-diazo-21 -hydroxy-20-methlypregnan-3-one has been reported as a potent, time-dependent inhibitor of steroid 5-.alpha.-reductase. Blohm, T. R., et al., (1980), Biochem. Biophys. Res. Comm. 95:273-280; U.S. Pat. No. 4,317,817, Mar. 2, 1982.
17.beta.-N,N-diethylcarbomoyl-4-methyl-4-aza-5-.alpha.-androstan-3-one is exemplary of a group of 4-aza steroid inhibitors of steroid 5-.alpha.-reductase described in U.S. Pat. No. 4,377,584 which issued Mar. 22, 1983, and in Liang, T., et al., (1983), J. Steroid Biochem. 19, 385-390. 17.alpha.-acetoxy-6-methylenepregn-4-ene-3,20-dione also has been shown to be a time-dependent inactivator of steroid 5-.alpha.-reductase. Petrow, V., et al., (1981), Steroids 38:121-140.
Other steroid 5-.alpha.-reductase inhibitors also have been described. U.S. Pat. No. 4,361,578 which issued Jun. 2, 1986, describes a class of homosteroid enzyme inhibitors. U.S. Pat. No. 4,191,759 discloses amides of 17.beta.-carboxy-4-androsten-3-one that are active as steroid 5-.alpha.-reductase inhibitors. Japanese Patents J60146855-A and J60116657-A disclose various aniline derivatives having numerous activities including 5-.alpha.-reductase inhibiting activity. Japanese Patent 60142941-A discloses phenyl-substituted ketones having 5-.alpha.-reductase inhibiting activity and European Patent EP173516-A discloses various phenyl-substituted amides having similar activity. Shiseido referenced terpene derivatives that are active inhibitors of steroid 5-.alpha.-reductase. Japanese Patent J59053417-A.
It has been postulated but never proven that the inhibition of steroid 5-.alpha.-reductase would result in a therapeutic effect on prostatic adenocarcinoma in mammals, Novel Approaches to Cancer Chemoterapy, Pub: Academic Press, Inc. (1984) Ch.8 V. Petrow and G. Padilla 5-.alpha.-reductase: A target enzyme for Prostatic Cancer, however, contrary evidence has also been published, Liang, T., et al., (1985), Endocrinology 117, No. 2: 571-579.
It has now been discovered that steroid 5-.alpha.-reductase inhibitors do have a therapeutic effect on prostatic adenocarcinoma of mammals.